The 3 “Rs” of multiple sclerosis (MS)—repair, remyelinate, and restore—spell out the goals of patients and physicians alike. MS is an incurable, immune-mediated, neurodegenerative disease of the central nervous system (CNS), and is thought to develop from unexplained autoimmune attacks directed at myelin (the covering on neurons) and glial cells, or “oligodendrocytes.” Neurodegeneration is evident early in the disease process and is characterized by mitochondrial dysfunction , energy failure, and neuronal and glial death.
While most new and investigational therapies aim to address immune dysfunction, a new idea—
one not involving immune dysregulation—is being explored in various studies: Are there agents, outside of traditional MS therapies, able to help with remyelination?
Mitochondria, oxidative stress, and MS
Neurons, oligodendrocytes, and oligodendrocyte precursor cells (OPCs) are particularly sensitive to oxidative stress. In MS, chronic inflammation and autoimmunity are key drivers of oxidative stress and secondary mitochondrial dysfunction.
Mitochondrial dysfunction is particularly relevant for neurodegeneration in MS. The observed dysfunction includes mitochondrial DNA damage, deficiency in mitochondrial DNA repair, reduced levels of antioxidants, and increased free radicals. Furthermore, the structure and number of mitochondria temporarily increase to accommodate the increased energy needs. Despite the attempted adaptation, energy failure ultimately occurs, resulting in a mismatch between energy needs or consumption and energy production. Neuroinflammation and the imbalance between energy consumption and generation create a vicious, continuous cycle that is characteristic in progressive MS. The energy failure is then associated with neuronal death, Wallerian degeneration, and subsequent accumulation of neurologic disability.
Current therapeutic landscape
While the therapeutic landscape for MS continues to evolve, the approved 20-plus therapies are primarily directed at the immune system. The overall goal is to modulate immune dysregulation and decrease inflammation. Current therapies may be able to control this macroscopic inflammatory activity.
However, current treatments only show modest effects on disease progression, and do not help to repair neurons, remyelinate axons, or restore function that was impaired due to disease progression. Some US Food and Drug Administration (FDA)–approved therapies are thought to modulate mitochondrial functions. For example, the class of fumarates (eg, dimethyl fumarate, diroximel fumarate, monomethyl fumarate) activates the nuclear factor erythroid 2 -related factor 2 (Nrf2) pathway in treated MS patients. However, it is unclear whether activation of the Nrf2 pathway is involved in the therapeutic effects of fumarates. A recent study challenged the importance of the Nrf2 pathway as a therapeutic target for fumarates. It showed that in an MS animal model, the effects of fumarates on disease control were similar between Nrf2 knock-out mice and the wild type, suggesting that fumarates' therapeutic effects are independent of the Nrf2 pathway . Furthermore, fumarates failed to show benefits in progressive forms of MS both clinically and on a biomarker level.
Metformin, the mitochondria, and neurodegeneration
Metformin (1,1-dimethylbiguanide) is an oral medication used primarily as first-line treatment for type 2 diabetes. However, due to its pharmacologic properties, mitochondrial effects, and the ability to cross the blood-brain barrier , scientists have shown recent interest in studying metformin in neurodegenerative diseases, including MS. Some of the potential benefits of metformin in neurodegenerative diseases include reduction of oxidative stress and countering mitochondrial dysfunction. It is known that metformin inhibits mitochondrial complex 1. Also, several studies have shown a positive effect of metformin on the reduction of oxidative stress and mitochondrial DNA regulation. Therefore, could metformin help combat mitochondrial dysfunction in MS or rejuvenate certain elements within the CNS in people with neurodegenerative diseases, including MS?
Oligodendrocytes and remyelination
Oligodendrocytes are cells responsible for myelinating axons within the CNS. Those cells originate from progenitors called OPCs. Interestingly, in humans, OPCs can mature into oligodendrocytes throughout their lifecycle, although to a much lesser extent in adults compared with children. However, therapeutic efforts to facilitate OPC maturation in vivo in MS lesions have failed thus far. Examples include high-dose biotin, the anti-LINGO-1 opicinumab, and the anticancer, retinoid-analog drug bexarotene.
So, what is behind these unfortunate failures? Some molecules (eg, biotin, opicinumab) failed to meet their clinical endpoints in randomized clinical trials, while others had severe toxicity that halted further clinical testing (eg, bexarotene). On the other hand, some molecules (eg, clemastine fumarate ), showed a modest yet promising effect on biomarkers in small clinical trials.
A discussion on molecule failures
What could explain the failure of molecules with such promising preclinical findings? One could argue that clinical trial designs may have been insufficient to detect small remyelinating effects. One could also argue that the maturation of OPCs into oligodendrocytes is too complex to facilitate using 1 molecule that may be an inhibitor of maturation or to activate/augment a facilitator of the maturation process. There are too many natural inhibitors and facilitators of OPC maturation, and an approach with combination therapy might have a better chance at achieving a favorable therapeutic effect.
Another piece of the complexity of OPC maturation is the recent discovery that, in humans, nonhuman primates, and other mammals, aged OPCs do not have the same capacity to mature into oligodendrocytes as young OPCs. There might be some clinical support here, as children with MS have more ability to recover from MS attacks than their adult counterparts. Also, the older the individual with MS is, the less likely they are to recover from MS attacks and the more likely they are to show signs of disease progression compared with their younger counterparts.
Theoretically, age-related recovery from clinical attacks may be partially explained by complications due to OPC aging. To this point, can we rejuvenate OPCs and restore their ability to mature into oligodendrocytes? Can metformin be the medicine that does so?
Interestingly, scientists could restore the ability of older OPCs to mature into oligodendrocytes, at least in the rodent model, through calorie restriction (eg, intermittent fasting) or by mimicking this state using metformin.
Metformin and the 3 “Rs”
One idea is to use metformin to create a biochemical state that allows OPCs to regain their ability to mature into oligodendrocytes in adult or aging individuals with MS. If that is achieved, other molecules may augment OPC' maturation or inhibit OPC maturation-inhibitors and become successful in promoting remyelination. A phase 2 clinical trial in the United Kingdom that is currently recruiting participants intends to investigate a combination of metformin and clemastine fumarate in 50 patients with relapsing-remitting MS. The goal is to learn whether metformin plus clemastine allows for therapeutic remyelination. In addition, a Canadian study is investigating metformin in children with MS. Two other studies are currently recruiting to study metformin in relapsing MS (Egypt) and progressive MS (United States).
Although testing metformin as a treatment for MS is still in the early stages, the scientific rationale is valid and supported by compelling preclinical evidence. Ongoing clinical trials will likely provide preliminary results on whether metformin will advance in clinical testing and provide clinically meaningful improvements for people living with MS.
If metformin is, in fact, a conditioning agent for use in remyelinating therapies, future clinical trials could be designed to administer metformin to rejuvenate OPCs before the administration of any molecule combination designed to facilitate OPC maturation. However, these trials will need to address an important issue: dosage. In type 2 diabetes, the typical daily dose is between 500 and 3000 mg per day. But in tests on rodents – which weigh about 10 grams – to rejuvenate OPCs, the doses of metformin were very high: 200 to 300 mg/kg. Given the body weight of humans and to avoid drug toxicity, the resulting smaller doses of metformin will take time to exert their potential therapeutic effect.
Should future research be successful in developing combination molecular therapies with diverse and synergistic therapeutic targets, then the 3 “Rs” in MS will allow for a fourth “R” to effectively succeed: repair, remyelinate, restore, and rehabilitate.